Childhood Kidney Diseases

Korean Society of Pediatric Nephrology (대한소아신장학회)
권호 표지
DOI QR코드

DOI QR Code

Vitamin D Dependent Rickets Type 1A Caused by CYP27B1 Mutation

  • Bak, Na Ry (Department of Pediatrics, Chonnam National University Medical School & Children's Hospital) ;
  • Song, Eun Song (Department of Pediatrics, Chonnam National University Medical School & Children's Hospital) ;
  • Yang, Eun Mi (Department of Pediatrics, Chonnam National University Medical School & Children's Hospital) ;
  • Kim, Chan Jong (Department of Pediatrics, Chonnam National University Medical School & Children's Hospital)
  • Received : 2019.04.03
  • Accepted : 2019.06.22
  • Published : 2019.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

Vitamin D dependent rickets type 1A (VDDR1A) is an autosomal recessive disorder caused by mutations in CYP27B1. Clinical findings are growth retardation, hypotonia, muscle weakness, hypocalcemic seizures, and radiological features of rickets. We aimed to present the VDDR1A case with a genetic study of CYP27B1. The 14-month-old boy was admitted to the hospital due to a seizure. Serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH), 25(OH) vitamin D, and 1,25(OH)2 vitamin D values were 5.1 mg/dL, 3.7 mg/dL, 705 IU/L, 429 pg/mL, 24.9 ng/mL, and 8.8 pg/mL, respectively. Radiological study showed cupping and fraying of the distal ulna and radius. The molecular genetic study revealed that the patient had a compound heterozygous mutation, $Phe443Profs^*24$ and c.589+1G>A, in CYP27B1. Genetic analysis of the family members presented that the mother was heterozygous for the mutation c.589+1G>A, and that the father was heterozygous for $Phe443Profs^*24$. The patient was treated with calcium lactate and calcitriol. Until now, six Korean patients with VDDR1A have been studied. Including this case, Korean patients with VDDR1A were found to have only three different mutations in 14 alleles, indicating that the mutation in the CYP27B1 gene is homogeneous in the Korean population.

Keywords

References

  1. Miller WL, Portale AA. Vitamin D $1{\alpha}$-hydroxylase. Trends Endocrinol Metab 2000;11:315-9. https://doi.org/10.1016/S1043-2760(00)00287-3
  2. Portale AA, Miller WL. Rickets due to hereditary abnormalities of vitamin D synthesis or action. In: Glorieux FH, Pettifor JM, Juppner H, eds. Pediatric bone. San Diego: Academic Press, 2003;583-98.
  3. Portale AA, Miller WL. Human 25-hydroxyvitamin D $1{\alpha}$-hydroxylase: cloning, mutations, and gene expression. Pediatr Nephrol 2000;14:620-5. https://doi.org/10.1007/PL00009639
  4. Breslau NA. Normal and abnormal regulation of 1,25(OH)2D synthesis. Am J Med Sci 1988;296:417-25. https://doi.org/10.1097/00000441-198812000-00009
  5. Kumar R, Harnden D, DeLuca HF. Metabolism of 1,25-dihydroxy vitamin D3: evidence for side-chain oxidation. Biochemistry 1976;15:2420-3. https://doi.org/10.1021/bi00656a027
  6. Demir K, Kattan WE, Zou M, Durmaz E, BinEssa H, Nalbantoglu O, et al. Novel CYB27B1 gene mutations in patients with vitamin D-dependent rickets Type 1A. PLoS One 2015;10:e0131376. https://doi.org/10.1371/journal.pone.0131376
  7. Edouard T, Alos N, Chabot G, Roughley P, Glorieux FH, Rauch F. Short-and long-term outcome of patients with pseudo-vitamin D deficiency rickets treated with calcitriol. J Clin Endocrinol Metab 2011;96:82-9. https://doi.org/10.1210/jc.2010-1340
  8. Kim CJ, Kaplan LE, Perwad F, Huang N, Sharma A, Choi Y, et al. Vitamin D 1alpha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency. J Clin Endocrinol Metab 2007;92:3177-82. https://doi.org/10.1210/jc.2006-2664
  9. Kim CJ. Vitamin D dependent rickets type I. Korean J Pediatr 2011;54:51-4. https://doi.org/10.3345/kjp.2011.54.2.51
  10. Cho JH, Kang E, Kim GH, Lee BH, Choi JH, Yoo HW. Long-term clinical outcome and the identification of homozygous CYP27B1 gene mutations in a patient with vitamin D hydroxylation-deficient rickets type 1A. Ann Pediatr Endocrinol Metab 2016;21:169-73. https://doi.org/10.6065/apem.2016.21.3.169
  11. Kitanaka S, Murayama A, Sakaki T, Inouye K, Seino Y, Fukumoto S, et al. No enzyme activity of 25-hydroxyvitamin D3 $1{\alpha}$-hydroxylase gene product in pseudovitamin D deficiency rickets, including that with mild clinical manifestation. J Clin Endocrinol Metab 1999;84:4111-7. https://doi.org/10.1210/jcem.84.11.6131
  12. Wang JT, Lin CJ, Burridge SM, Fu GK, Labuda M, Portale AA, et al. Genetics of vitamin D $1{\alpha}$-hydroxylase deficiency in 17 families. Am J Hum Genet 1998;63:1694-702. https://doi.org/10.1086/302156
  13. Malloy PJ, Feldman D. Genetic disorders and defects in vitamin D action. Rheum Dis Clin North Am 2012;38:93-106. https://doi.org/10.1016/j.rdc.2012.03.009
  14. Dursun F, Ozgurhan G, Kirmizibekmez H, Keskin E, Hacihamdioglu B. Genetic and clinical characteristics of the patients with vitamin D dependent rickets type 1A. J Clin Res Pediatr Endocrinol 2018 Oct 4doi: 10.4274/jcrpe.0121.
  15. Akerstrom G, Hellman P, Hessman O, Segersten U, Westin G. Parathyroid glands in calcium regulation and human disease. Ann N Y Acad Sci 2005;1040:53-8. https://doi.org/10.1196/annals.1327.005
  16. Acar S, Demir K, Shi Y. Genetic causes of rickets. J Clin Res Pediatr Endocrinol 2017;9:88-105.
  17. Wang X, Zhang MY, Miller WL, Portale AA. Novel gene mutations in patients with 1alpha-hydroxylase deficiency that confer partial enzyme activity in vitro. J Clin Endocrinol Metab 2002;87:2424-30. https://doi.org/10.1210/jcem.87.6.8534
  18. Nishikawa M, Yasuda K, Takamatsu M, Abe K, Nakagawa K, Tsugawa N, et al. Generation of 1,25-dihydroxyvitamin D3 in CYP27B1 knockout mice by treatment with 25-hydroxyvitamin D3 rescued their rachitic phenotypes. J Steroid Biochem Mol Biol 2019;185:71-9. https://doi.org/10.1016/j.jsbmb.2018.07.012
  19. Fu GK, Lin D, Zhang MY, Bikle DD, Shackleton CH, Miller WL, et al. Cloning of human 25-hydroxyvitamin D 1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type I. Mol Endocrinol 1997;11:1961-70. https://doi.org/10.1210/mend.11.13.0035
  20. Fu GK, Portale AA, Miller WL. Complete structure of the human gene for the vitamin D $1{\alpha}$-hydroxylase, $P450c1{\alpha}$. DNA Cell Biol 1997;16:1499-507. https://doi.org/10.1089/dna.1997.16.1499